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Antiviral agents
until the 1950s it was believed not to be susceptible to ‘antibiotic’ therapy. This dogma was reversed with the discovery of 5-iodo-20 -deoxyuridine (idoxurine) (Prusoff, 1959), and began the time of antiviral chemotherapy discovery ;Idoxuridine: An early antiviral, which was cytoxic selectivity was developed initial by showing the dome deoxyguanosine analogues selectively inhibited Herpes Simplex type 1 inhibition of viral nucleic acid polymerases by nucleoside analogues, is the single most important chemotherapeutic interaction to date, In response to the antiviral management of HIV patients, a new approach, unthinkable in the 1950s was the use of combinations of two or more compounds. De Clercq, E. and Field, H. J. (2006) Discovery of novel antiviral agents Traditionally large numbers of agents are tested against assays for their antiviral effects. ;plaque assays : a means of growing virus in culture and then testing various substances for their inhibitory effect. Plaque assays are convenient and provide high throughput screening for compounds disadvantages of plaque assays is they provide no information on the functional process, and that some virus cannot be grown easily in culture. ;Viral enzyme assays: making use of cloning the proteins which the virus express in order to test drugs which are active against specific viral protein targets. ;Animal models: used to test candidate compounds in vivo Discovery of viral drug targets x-ray crystallography has been the traditional method of discovering/"solving" the 3-d structure of the virus and its host cell targets gene sequencing is now becoming the more obvious way to determine the structure and function of the viral component proteins and enzymes. the transcription and replication of nucleic acids, are a major target for antivirals. ;viral polymerases: enzymes that have vital functions in the replication of the viral nucleic acids 4 basic principles of antiviral agents drug targets # target is important to virus lifecycle # dissimilar to human proteins of equivalent function # common to many viruses # interfere at an early stage in the viral-infection lifecycle the inhibition of viral nucleic acid polymerases by nucleoside analogues, which is the single most important chemotherapeutic interaction to date, Challand, R. and Young, R. (1997) ;Oligonucleotides:An oligonucleotide (from Greek prefix oligo-, "having few, having little") is a short nucleic acid polymer, typically with fifty or fewer bases. Oligonucleotides readily bind, in a sequence-specific manner, to their respective complementary oligonucleotides, DNA, or RNA to form duplexes or, less often, hybrids of a higher order. There are no ‘class effects’ among antiviral nucleosides. = nucleoside analogues = Nucleic acid synthesis nucleoside triphosphate monomers all antiviral nucleosides are in effect pro-drugs, since they require activation in the cell before they can exert their effect. NTPs are built up from parent nucleosides by adding phosphate units by kinases all viruses possess polymerases strategies for inhibitors therefore are to # block viral polymerase # replace the nucleoside with a non-functional analogue which terminates the nucleic acid chain acyclovir the drug that pioneered the control of infections due to herpes viruses, was the first selective antiviral agent. deoxyguanosine analogues selectively inhibited Herpes Simplex type 1 has very high selectivity due to requiring a phosphorlyzation step that is specific to the viral enzyme has poor bioavailability relatively poor solubility Valaciclovir prodrug of ac;ovir = Protease inhibitors = viral protolytic enzymes are a drug target for antivirals, particularly when the protease is critical for the viral lifecucle and distinct from the host a number of protease inhihibitors are approved as antiviral agents http://en.wikipedia.org/wiki/Protease_inhibitor_%28pharmacology%29 Ribavirin Ribavirin, licensed in 1986 Tamiflu Category:Infectious Disease Category:Viruses